Journal of Alzheimer's Disease - Volume 62, issue 2

Authors: Milne, Richard | Bunnik, Eline | Diaz, Ana | Richard, Edo | Badger, Shirlene | Gove, Dianne | Georges, Jean | Fauria, Karine | Molinuevo, Jose-Luis | Wells, Katie | Ritchie, Craig | Brayne, Carol

Article Type: Review Article

Abstract: In clinical trials which target pathophysiological mechanisms associated with Alzheimer’s disease, research participants who are recruited based on biomarker test results should be informed about their increased risk of developing Alzheimer’s dementia. This paper presents the results of a qualitative focus group study of attitudes and concerns toward learning information about biomarker-based risk status among healthy research participants in the United Kingdom and Spain and people with dementia and their supporters/caregivers from countries represented in the European Working Group of People with Dementia of Alzheimer Europe. The study identified expectations related to learning risk status and preferences related to the …content, quality, and follow-up of the disclosure process. The latter emphasize distinctions between risk and diagnoses, the importance of clear information about risk, and suggestions for risk reduction, as well as expectations for follow up and support. The implications of these preferences for practice are discussed. Providing details of research participants’ experience and views may serve as a guide for the development of processes for the responsible disclosure of Alzheimer’s disease biomarkers. Show more

Keywords: Biomarkers, disclosure, focus groups, ethics, qualitative research

DOI: 10.3233/JAD-170813

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 487-498, 2018

Authors: Stites, Shana D.

Article Type: Research Article

Abstract: Richard Milne and colleagues (2018) present the results of a study to discover what cognitively unimpaired research participants hope to gain by learning Alzheimer’s disease (AD) biomarker results and the associated risk for AD dementia. Their results are useful to develop procedures to safely disclose AD biomarker results in prevention trials. They also foreshadow the ethical and pragmatic challenges of using AD biomarkers in routine clinical practice. What is currently known is largely from studies of cognitively unimpaired or mildly impaired individuals who learned they had genetic markers of AD. Little is known about learning biomarker results. Milne and colleagues …found that participants expect they will routinely learn risk reduction strategies and have access to follow up care. Can we meet these expectations? Mixed evidence supports effective therapies for delaying symptoms of AD and virtually nonexistent evidence guides prevention of AD. Healthcare resources, including follow-up, are designed to manage patients who have clinical symptoms—not the potentially large numbers of unimpaired individuals. To meet these needs, researchers who disclose AD biomarker results to cognitively unimpaired research participants may have an obligation to develop effective interventions and provide follow up care. Show more

Keywords: Alzheimer’s disease, biomarkers, early diagnosis, ethics, result disclosure

DOI: 10.3233/JAD-171089

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 499-502, 2018

Authors: Croze, Marine L. | Zimmer, Luc

Article Type: Review Article

Abstract: Atmospheric pollution is a well-known environmental hazard, especially in developing countries where millions of people are exposed to airborne pollutant levels above safety standards. Accordingly, several epidemiological and animal studies confirmed its role in respiratory and cardiovascular pathologies and identified a strong link between ambient air pollution exposure and adverse health outcomes such as hospitalization and mortality. More recently, the potential deleterious effect of air pollution inhalation on the central nervous system was also investigated and mounting evidence supports a link between air pollution exposure and neurodegenerative pathologies, especially Alzheimer’s disease (AD). The focus of this review is to highlight …the possible link between ozone air pollution exposure and AD incidence. This review’s approach will go from observational and epidemiological facts to the proposal of molecular mechanisms. First, epidemiological and postmortem human study data concerning residents of ozone-severely polluted megacities will be presented and discussed. Then, the more particular role of ozone air pollution in AD pathology will be described and evidenced by toxicological studies in rat or mouse with ozone pollution exposure only. The experimental paradigms used to reproduce in rodent the human exposure to ozone air pollution will be described. Finally, current insights into the molecular mechanisms through which ozone inhalation can affect the brain and play a role in AD development or progression will be recapitulated. Show more

Keywords: Alzheimer’s disease, atmospheric pollution, neuroinflammation, oxidative stress, ozone

DOI: 10.3233/JAD-170857

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 503-522, 2018

Authors: Zádori, Dénes | Veres, Gábor | Szalárdy, Levente | Klivényi, Péter | Vécsei, László

Article Type: Review Article

Abstract: The pathomechanism of Alzheimer’s disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been …implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options. Show more

Keywords: Alzheimer’s disease, glutamate excitotoxicity, 3-hydroxy-L-kynurenine, kynurenic acid, kynurenine pathway, mitochondrial dysfunction, neuroinflammation, quinolinic acid, tryptophan metabolism

DOI: 10.3233/JAD-170929

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 523-547, 2018

Authors: Szablewski, Leszek

Article Type: Review Article

Abstract: Gut microbiota plays a crucial role in human health and disease. The alterations in the composition of gut microbiota may cause the onset of certain human pathologies. One of these is Alzheimer’s disease (AD). High-fat diets, administration of antibiotics, lack of probiotics and/or prebiotics in diet increase the risk of AD. On the other hand, modulation of the composition of gut microbiota may decrease the risk of AD and be able to slow down the progression of AD.

Keywords: Alzheimer’s disease, dysbiosis, gut microbiota, metabolic endotoxemia, physiology

DOI: 10.3233/JAD-170908

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 549-560, 2018

Authors: Smith, A. David | Refsum, Helga | Bottiglieri, Teodoro | Fenech, Michael | Hooshmand, Babak | McCaddon, Andrew | Miller, Joshua W. | Rosenberg, Irwin H. | Obeid, Rima

Article Type: Editorial

Abstract: Identification of modifiable risk factors provides a crucial approach to the prevention of dementia. Nutritional or nutrient-dependent risk factors are especially important because dietary modifications or use of dietary supplements may lower the risk factor level. One such risk factor is a raised concentration of the biomarker plasma total homocysteine, which reflects the functional status of three B vitamins (folate, vitamins B12, B6). A group of experts reviewed literature evidence from the last 20 years. We here present a Consensus Statement, based on the Bradford Hill criteria, and conclude that elevated plasma total homocysteine is a modifiable risk factor for …development of cognitive decline, dementia, and Alzheimer’s disease in older persons. In a variety of clinical studies, the relative risk of dementia in elderly people for moderately raised homocysteine (within the normal range) ranges from 1.15 to 2.5, and the Population Attributable risk ranges from 4.3 to 31%. Intervention trials in elderly with cognitive impairment show that homocysteine-lowering treatment with B vitamins markedly slows the rate of whole and regional brain atrophy and also slows cognitive decline. The findings are consistent with moderately raised plasma total homocysteine (>11 μmol/L), which is common in the elderly, being one of the causes of age-related cognitive decline and dementia. Thus, the public health significance of raised tHcy in the elderly should not be underestimated, since it is easy, inexpensive, and safe to treat with B vitamins. Further trials are needed to see whether B vitamin treatment will slow, or prevent, conversion to dementia in people at risk of cognitive decline or dementia. Show more

Keywords: Homocysteine, folate, vitamin B12, cobalamin, vitamin B6, cognitive impairment, dementia, Alzheimer’s disease, brain atrophy, risk-factor, causation

DOI: 10.3233/JAD-171042

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 561-570, 2018

Authors: Tan, Daniel C.S. | Yao, Sherilyn | Ittner, Arne | Bertz, Josefine | Ke, Yazi D. | Ittner, Lars M. | Delerue, Fabien

Article Type: Short Communication

Abstract: Alzheimer’s disease and other dementias present with tau pathology. Several mouse lines with knockout of the tau-encoding Mapt gene have been reported, yet findings often differed between lines and sites. Here, we report a new tau knockout strain (tauΔex1 ), generated by CRISPR/Cas9-mediated genome editing of intron -1/exon 1 of Mapt in C57Bl/6J mice. TauΔex1 mice had no overt phenotype, but, in line with previous models, they showed a significantly reduced susceptibility to excitotoxic seizures, with normal memory formation in young mice. This new in vivo resource will be made freely available to the research community.

Keywords: C57Bl/6, CRISPR, gene knockout, mouse, tau

DOI: 10.3233/JAD-171058

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 571-578, 2018

Authors: Sanders, Marit L. | Stuckenschneider, Tim | Devenney, Kate E. | Lawlor, Brian | Schneider, Stefan | Olde Rikkert, Marcel G.M. | on behalf of the NeuroExercise Study Group

Article Type: Short Communication

Abstract: Prevention trials in subjects with mild cognitive impairment (MCI), especially lifestyle interventions, can be difficult to carry out, particularly the recruitment and retention of subjects. We experienced these challenges in our multi-site one-year exercise trial in MCI, NeuroExercise. Trial recruitment rates differed significantly across sites; the non-medical sport university site, providing free access to a range of group exercise in a sports environment, proved far more successful than memory clinics linked to hospitals. This suggests that non-medical settings and a non-medical research community facilitating physical activities may be important factors in recruitment of subjects with MCI for large prevention trials.

Keywords: Attrition, exercise, mild cognitive impairment, prevention, recruitment, selection

DOI: 10.3233/JAD-171083

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 579-581, 2018

Authors: Alexander, Courtney | Zeithamova, Dagmar | Hsiung, Ging-Yuek R. | Mackenzie, Ian R. | Jacova, Claudia

Article Type: Short Communication

Abstract: We tested the potential of task-based functional neuroimaging as a biomarker of emerging prefrontal brain changes in progranulin (GRN ) mutations carriers. Five GRN mutation carriers free of frontotemporal dementia (FTD) and 11 non-carriers from families with FTD-GRN underwent functional MRI while solving matrix-reasoning problems. Mutation carriers displayed slower responses for more difficult problems and lower lateral prefrontal activation across all problems. Overall task-evoked posterior ventrolateral prefrontal activation predicted mutation status with 100% sensitivity and 91% specificity. Volumetric differences did not account for activation differences. Prefrontal activation may have utility as a biomarker in GRN mutation.

Keywords: Frontotemporal dementia, functional MRI, mutation carriers, predementia, prefrontal cortex, progranulin, relational reasoning

DOI: 10.3233/JAD-170716

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 583-589, 2018

Authors: King, Jillian L. | Wong, Aimée A. | Brown, Richard E.

Article Type: Short Communication

Abstract: Visual impairments and retinal abnormalities occur in patients with Alzheimer’s disease (AD) and in mouse models of AD. It is important to know the visual ability of mouse models of AD to ensure that age-related cognitive deficits are not confounded by visual impairments. Using OptoMotry, the spatial frequency thresholds of male and female 3xTg-AD mice did not differ from their B6129SF2 wildtype controls between 1–18 months of age, but females had higher spatial frequency thresholds than males. However, the differences were quite small, and the visual ability of all mice was comparable to that of C57BL/6 mice.

Keywords: 3xTg-AD mice, aging, Alzheimer’s disease, mice, mouse models, OptoMotry, sex differences, vision

DOI: 10.3233/JAD-170805

Citation: Journal of Alzheimer's Disease, vol. 62, no. 2, pp. 591-596, 2018